As drug trials fail, Alzheimer's researchers look toward prevention

Hopes for coming up with an effective drug treatment for Alzheimer's disease took another hit last week when two once-promising drugs failed to improve patient cognition during pivotal Phase 3 clinical trials.

With millions of baby boomers expected to suffer severe cognitive decline over the next few decades, the drug industry's repeated failure to come up with a successful intervention is putting renewed pressure on researchers to identify and develop preventive measures that aging adults can take to forestall the debilitating descent into dementia.

“We should begin to direct more efforts toward risk factors that may be modifiable,” said Dr. Eric Larson, vice president of research for Group Health Research Institute in Seattle. He's been outspoken about the need to refocus attention from drugs to things such as decreasing diabetes and stroke rates. “My personal belief is that it will not be possible to find a single pill. It's going to be a combination of things we do to delay chronic diseases that will allow people to live out their lives fully before being struck by conditions like Alzheimer's.”

Healthcare providers, government payers and families have a huge stake in the pace and success of Alzheimer's research. Failure to come up with successful treatments or preventive measures will place growing financial pressure on those tasked with caring for the increasing numbers of mentally challenged older Americans, most of whom won't have long-term care insurance.

For them, there was no good news last week. Two beta amyloid inhibitors, solanezumab and bapineuzumab, did not achieve improved cognition in patients with mild to moderate Alzheimer's, according to studies in the New England Journal of Medicine. The beta amyloid protein is a main component of plaque that builds up on the brain cells of Alzheimer's patients.

While an accompanying editorial called for continuing research into beta amyloid inhibitors, other researchers argued that research-and-development activities are focusing too much on drugs and overlooking promising findings in areas where people have more control.

Half of the factors that contribute to cognitive decline are linked to behavioral, dietary and environmental factors, they say. During a medical innovation summit last year, Dr. Jeff Cummings, director of the Cleveland Clinic's Center for Brain Health, said while many risks for developing the disease are linked to uncontrollable factors like age and genetics, studies have pointed to other factors.

Alzheimer's has sometimes been referred to as “type 3 diabetes” because of its strong link to obesity. Excess body weight elevates brain proteins linked to a person's risk of developing the disease, Cummings said.

There are 94 medicines in development in the U.S. for Alzheimer's, according to PhRMA's 2013 research and development report. Between 1998 and 2011, 101 attempts to create Alzheimer's drugs were unsuccessful. Only three were approved, and they have very modest impact on the progression of the disease.

A search for “Alzheimer's” on the government's clinical trial registry renders more than 1,300 studies in various stages of development. While many of those studies are traditional drug trials, a significant number are looking at everything from brain training to dietary changes to slowing the progression of the disease.

A study in Neurology found older women with higher levels of omega-3 fatty acids had larger total brain volumes. To the researchers, that indicated better preservation of brain health.

“These higher levels of fatty acids can be achieved through diet,” the study's lead author said. “Results suggest that the effect on brain volume is the equivalent of delaying the normal loss of brain cells that comes with aging by one to two years.”

MH Takeaways

With new drugs for Alzheimer's far from discovery, some researchers push for more emphasis on mitigating the behavioral, dietary and environmental factors associated with greater incidence of the disease.

Even keeping your “good” cholesterol elevated and your “bad” cholesterol under control may be beneficial. Doing so lowers the level of amyloid plaque in the brain, according to a study published in JAMA Neurology. The study authors said understanding this link could offer new approaches to slowing plaque deposits and possibly reduce the incidence of Alzheimer's disease.

Researchers aren't calling it quits on studies of beta amyloid inhibitors and other pharmaceutical therapies. Authors of the bapineuzumab paper suggest future research focus on use of the drug in patients before the onset of symptoms, noting that use of the treatment after dementia has already developed may be too late. “We remain encouraged and excited by the findings,” wrote a spokesperson for Eli Lilly, manufacturer of solanezumab, which is conducting another Phase 3 study of the drug.

The next wave of studies is likely to focus on the tau protein, said Dr. Gary Kennedy, a geriatric psychiatrist at the Montefiore Medical Center in New York. These proteins, normal in the body, are overpopulated in the brains of patients with Alzheimer's disease. When they start to proliferate, cell death begins. Efforts to stop that process are next on the horizon, he said.

Still, other researchers and clinicians warn against putting too much faith in the search for a magic bullet to slow or reverse the brain deterioration process. “To think that targeting a single abnormal protein is the only way, or even an effective way to deal with this disease, may be naive and simplistic,” said Larson of the Group Health Research Institute. “You'll continually be disappointed.”

The bottom line is that more research is needed—and fast. Age is the biggest risk factor for developing the disease.

“We need a broad portfolio of research that not only looks at plaques and tangles in the brain, but at the multiple risk factors that may impact Alzheimer's,” said Dean Hartley, director of science initiatives for the Alzheimer's Association. He hopes the Obama administration's recent appropriation of $122 million toward research, education, outreach and caregiver support during fiscal 2014 will help. “The only way we are going to find answers is through research, and we still don't have enough dollars going toward this disease,” he said.